Luminal strictures, such as urethral or ureteral strictures, represent a vexing problem for urologists. Urethral strictures result from spongiofibrosis, most of which is composed of type I collagen, and are due to the imbalance of collagen formation and destruction following urethral injury (Baskin et al. J. Urol. 1993. August 150 (2 Pt 2): 642-7). Urethral strictures are commonly treated with dilation and/or incision followed by stenting, but such techniques have suffered from high failure rates. The use of pharmacologic agents to prevent stricture formation (e.g. MMC, steroids, colchicine) have improved treatment results only marginally.
Short urethral strictures are typically treated with a direct visual internal urethrotomy (DVIU), or incision of the stricture, followed by catheter stenting for approximately 4 days, in hopes that the new scar will heal around the stent, leaving a large caliber urethra. Unfortunately, wound healing cannot be well controlled, and the new incision heals via the deposition of type-I collagen, which may contract, causing a high rate of stricture recurrence.
Orally administered and locally injected halofliginone has been shown to prevent collagen deposition and stricture formation in the ureter and urethra in animal models of urologic strictures (Turk et al. J. Endourol. 2000 March; 14(2):145-7; Nagler et al. J. Urol. 2000 November; 164(5):1776-80; Jaidane et al. J. Urol. 2003 November; 170(5):2049-52). Oral doses of up to 3.5 mg/day were administered to patients with solid tumors with minimal ill effects (Jianng et al. Antimicrob Agents Chemother. 2005 March; 49(3):1169-76).
However, oral administration or administration by injection is not ideal. There is need for new approaches to alleviate urethral strictures and other problems associated with medical interventions.